We hypothesize that donor and recipient statin treatment is an effective and innovative approach to lower the risk of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation (HCT). In a large retrospective analysis of outcomes among 567 recipients of HLA-identical HCT, we found that prior treatment of donors with statins, a class of drugs with cholesterol-lowering and immune-modulating effects, was associated with profound protection against severe acute GVHD. The protective effect was restricted to recipients given cyclosporine (CSP)-based postgrafting immunosuppression and not observed among those given tacrolimus (TAC). These findings, if confirmed, will have a significant impact on improving the safety of clinical HCT. Based on these findings, we propose to optimize a statin regimen that has been shown to be GVHD-protective in the canine HCT model (Aim 1) and translate this regimen into a clinical phase II study (Aim 2). Finally, by using T cells from statin-treated human stem cell donors, in vitro studies will be performed aimed at defining the GVHD-protective mechanisms (Aim 3). In Aim 1, before proceeding to a clinical trial, we will optimize the statin regimen that has been shown to confer GVHD-protection in the canine HCT model. We will focus on two important questions that will instruct the design of the clinical trial: (i) Can the duration of donor statin-treatment be shortened to less than 3 weeks without compromising efficacy; and (ii) is it sufficient to treat only the donor with a statin before HCT (and not the recipient) for the GVHD-protective effect to be operative? In Aim 2, we will initiate a prospective phase II clinical trial aimed at assessing efficacy and safety of donor (and potentially recipient) statin conditioning for the prevention of acute GVHD. In addition, in an observational cohort study of 4,500-6,000 patients approved by the Center for International Blood and Marrow Transplant Research (CIBMTR), unrelated donor statin use will be assessed prospectively and correlated with transplantation outcomes. In Aim 3, we will use in vitro assays to determine how T cell function is altered by exposure to statins in vivo. By using blood samples from statin-treated stem cell donors participating in the clinical trial (Aim 2), we will test the hypothesis that statins impair sustained T cell activation and synergize with CSP (but not TAC) in preventing GVHD by compromising mitochondrial function. Alternatives to this hypothesis will also be explored. The collective findings derived from these studies will provide preliminary information that will be needed in order to evaluate the merits of a more patient- and resource-intensive phase III clinical trial.